Treatment optimisation. Dose optimisation of antiretrovirals

54
Sandro Vento Department of Internal Medicine, Faculty of Medicine, University of Botswana

Transcript of Treatment optimisation. Dose optimisation of antiretrovirals

Page 1: Treatment optimisation. Dose optimisation of antiretrovirals

Sandro Vento

Department of Internal Medicine, Faculty of Medicine, University of Botswana

Page 2: Treatment optimisation. Dose optimisation of antiretrovirals

Out of 34 million people currently infectedwith HIV/AIDS, over 90% live in low andmiddle income countries

Although around 9 million people havebeen started on antiretroviral treatment inthese countries, at least additional 11million people in low and middle incomecountries are eligible for treatment but arenot receiving it

Page 3: Treatment optimisation. Dose optimisation of antiretrovirals

The vast majority of the 21 million peopleinfected with HIV, but currently untreated,in developing countries will requireantiretrovirals at some time in the future, ifthey are identified and tested

In addition, there are an estimated 2.5million new HIV infections every year

Page 4: Treatment optimisation. Dose optimisation of antiretrovirals

There is therefore a need to treat 20 millionpeople with antiretrovirals in low or middleincome countries within the next 5 years

Funding is being cut and will be difficult totreat so many patients

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Drug costs are accounting for as much as60% of antiretroviral treatment program costsin many countries

Active product ingredient production costsare the biggest driver of antiretroviral drugprices among generic manufacturers

A given percentage reduction in dosage willtranslate into a virtually equivalentpercentage reduction in drug pricing

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Even small reductions in the annualper-patient cost of treatment wouldlead to important reductions in theglobal cost of HIV treatment

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From: Andrew Hill,

Curr Opin HIV AIDS 2013; 8: 34-40.

Page 8: Treatment optimisation. Dose optimisation of antiretrovirals

The dose of zidovudine was reduced from1,500 mg daily to 600 mg daily

The dose of didanosine was reduced from750 mg to 400 mg daily

The dose of stavudine was reduced from 40mg to 30 mg twice daily

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During the dose-selection phase of HIV drugdevelopment, clinical trials of 30-100patients per arm are used to evaluate theefficacy and safety of several doses

In most cases, these trials show similar levelsof efficacy between a range of doses

In these situations, pharmaceuticalcompanies tend to progress with higherdoses

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To maximise the potential for long-term

efficacy and possibly to ensure efficacy even

when drug interactions lower the

concentration of the new antiretroviral

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Choosing higher doses can compromisepatient safety

The higher doses are more expensive tomanufacture

Page 12: Treatment optimisation. Dose optimisation of antiretrovirals

The DMP-005 trial of efavirenz wasconducted in 1996-1997, was presented atthe 5th CROI meeting in Chicago, February1998, but was never published

137 naïve patients were randomized to 24weeks of treatment with zidovudine pluslamivudine with efavirenz at doses of 200mg, 400 mg or 600 mg once daily, ormatching placebo

Page 13: Treatment optimisation. Dose optimisation of antiretrovirals

There was no difference in HIV RNAsuppression rates between the three doses ofefavirenz. These efficacy results weresustained to week 24

6 patients withdrew from the efavirenz 600mg once daily arm owing to adverse events,versus none from the efavirenz 200 mggroup

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Genetic analysis of patients receiving efavirenzshowed that plasma drug levels could be up tothree times higher for those with a certainCYP2B6 allelic variant, seen most often inAfricans.1

The CYP2B6*6 allele associated with slowefavirenz metabolizer phenotype is e.g. commonin Batswana with a prevalence over 30%.2

1Haas D et al. AIDS 2004; 18: 2391-400.2Gross R et al. J Acquir Immune Defic Syndr 2008; 49: 336-37.

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In an analysis of 255 Dutch patients, femalesand those with low body weight hadsignificantly higher efavirenz drug levels

Burger D et al. Br J Pharmacol 2006: 61: 148-54

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The mean body weight for patients in theDMP-005 trial was higher than would beexpected for an Asian or African naïve patientpopulation, where efavirenz drug levels arealso expected to be higher

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33 HIV-infected patients treated with twoNRTIs plus EFV at reduced dose

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Group 1:

Patients who reduced efavirenz to 400 mgafter 33-119 months (mean 66.4) on fulldose and when HIV-RNA was < 50 copies/mL

EFV was reduced, due to sleep disturbancesand on the basis of pharmacokinetic data, to400 mg in all but one patient (switched to200 mg)

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Group 2:

Patients who had a mean 35.4 months (range21-60) treatment duration and HIV-RNA < 50copies/mL before efavirenz reduction to 400mg by physicians in charge due to sleepdisturbances and prior to knowingpharmacokinetic data

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Group 3:

Patients naïve to antiretrovirals, with a pretreatmentmean HIV RNA level of 104,529 copies/mL

4 patients were started on EFV 400 mg by thephysicians in charge, 4 had decided to take only 400mg and 2 only 200 mg despite being prescribed fulldose

The latter 6 patients informed physicians of theirdecision after few months on the reduced doses, andthen PK analysis was performed

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Only one virological failure has been observedthus far in the patients on reduced EFV dose

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Patients

groups

(No.)

Females

/ Males

Caucasian

s

/Africans

Mean

age

(range)

Mean CD4

cells before

EFV at

reduced dose

Mean CD4 cell

counts after EFV

at reduced dose

(months)

Mean (range)

EFV Ctrough

before reduced

dose

Mean (range)

EFV Ctrough 6

months after

starting

reduced dose

1 (16) 1/15 16/0 41 yrs

(30-

61)

694/µL 753/µL

(33-37)

2380.5

ng/mL

(1181-6585)

1569.1

ng/mL(193-

3934)

2 (7) 2/5 6/1 48 yrs

(27-

68)

612/µL 722/µL

(32-34)

3045.1

ng/mL

(913-6872)

1049.1

ng/mL

(402-2376)

3 (10) 4/6 10/0 48 yrs

(34-

67)

300/µL 814/µL

(31-113)

N.A. 1579.9

ng/mL

(1046-2163)

*

*in 2 patients Ctrough was determined 69 and 72 months after startingEFV respectively

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After 27 months on a reduced efavirenz dose(400 mg), HIV RNA raised to 76 copies/mL

Efavirenz increased to 600 mg

HIV RNA < 40 copies/mL two weeks later

Efavirenz decreased again to 400 mg after 10months

HIV RNA continues to be < 40 copies/mL twomonths later

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Although 10 patients (in groups 1 and 2) hadefavirenz levels below Minimum EffectiveConcentration after dose reduction, only onevirological failure has been observed over anup to 37 months follow-up period

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Previous studies also questioned relationshipbetween plasma levels and efficacy

The FOTO study* suggested that long-termmaintenance phase of an efavirenz-containingfully suppressive first-line regimen could requirelower pharmacological pressure

*Cohen CJ et al. Pilot study of a novel short-cycle antiretroviral treatment

Interruption strategy: 48-week results of the five-days-on, two-days-off (FOTO) study.

HIV Clin Trials 2007; 8: 19-23.

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Encore1 study design

A randomized, double-blind, placebo-controlled, non-inferiorityclinical trial to compare the safety and efficacy of reduced doseEFV with standard dose EFV plus 2N(t)RTI in ART-naïve HIV-infected individuals over 96 weeks

Patient population

ART-naïve HIV-infected adults with no prior AIDS, plasma HIV-1RNA (pVL) >1,000 copies/mL, 50 <CD4+ T cells/µL <500,creatinine clearance ≥50 mL/min, no pregnancy or nursingmothers

Randomisation

I. TDF/FTC + 400 mg EFV qd(2 x 200 mg EFV + 1 x 200 mg matched placebo)

II. TDF/FTC + 600 mg EFV qd

(3 x 200 mg EFV)

1:1 (400mg:600mg), stratified by clinical site and screening pVL

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In the ENCORE1 study, a significantly lower

number of recipients of the efavirenz 400 mg

regimen reported adverse events definitely or

probably related to the study drug (118 [37%])

compared with efavirenz 600 mg (146 [47%]);p=0.008 .

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Using a 400 mg dose of efavirenz wouldlower the cost by $16 per person per year inlow income countries

As several million people are likely to useefavirenz in low income countries, this dosereduction could translate to a cost saving ofup to $70-130 million over 5 years

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The Abbott 720 trial evaluated three doses oflopinavir/ritonavir in treatment naïvepatients.

The study population in this Phase 2 trial hada high baseline body weight and wascomposed predominantly of male Caucasians.

Murphy R et al. ABT-378/ritonavir plus

stavudine and lamivudine for the treatment of antiretroviral-naïve

adults with HIV-1 infection: 48 week results. AIDS 2001; 15: 1-9.

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Strong efficacy of the 200/100 mg twice dailydose seen in PI-naïve patients

400/100 mg twice daily dose was chosen forPhase 3 development, in an attempt to targetboth PI-naïve and PI pre-treated patients with asingle uniform dose

Possibility of using a lower lopinavir/r dose forPI-naïve patients (including those failing first-line NNRTI-based ART in developing countries)

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If the 200/50 mg twice daily dose could beestablished as efficacious, the cost oflopinavir/ritonavir could be lowered from$400 to $220 per person-year in Africancountries

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Experience in six HIV-1–infected patients (4women) on reduced dose oflopinavir/ritonavir followed in the OutpatientClinic, Infectious Diseases Unit, University ofVerona

Lattuada E, Lanzafame M, Vento S. Efficacy of Lopinavir-Ritonavir Reduced Dose

in HIV-Infected Patients. AIDS Patient Care and STDs 2011; 25: 455-56.

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Page 37: Treatment optimisation. Dose optimisation of antiretrovirals

Potent protease inhibitor, currently administeredat the dose of either 300 mg in combination with100 mg of ritonavir or, less frequently, 400 mgonce daily in treatment-naïve patients

In HIV-1 infected Thai adults a pilot study ofatazanavir/ritonavir at dose of 200/100 mg dailyshowed the same plasma atazanavir drug levelsas in Caucasian patients given 300/100 mg dailyof atazanavir/ritonavir*

*Avihingsanon A et al. Clin Pharmacol Ther 2009 ;85: 402-08.

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Antiretroviral agent

Reference Method Doses studied Outcome Conclusion

Zidovudine Volberding et al. 1990

Randomised, double-bind study

1,500 mg daily vs 500 mg

daily vs placebo

Progression to AIDS lower in the 500 mg and in the

1,500 mg than in the placebo

group

Lower dose showed equal efficacy and improved safety

Stavudine Hill et al. 2007

Meta-analysis 30 mg twice daily vs 40 mg

twice daily

Lower rates of peripheral neuropathy

and lipoatrophy with lower

dose

Lower dose showed equal efficacy and improved safety

McComsey et al. 2008

Randomised ,open-label study

20 mg twice daily vs 40 mg twice daily, and

15 mg twice daily vs 30 mg

twice daily

Improvement in

mitochondrial indices with lower doses

Lower dose showed equal efficacy and improved safety

Efavirenz Hicks et al. 1998

Double-blind, placebo-controlled phase 2 clinical trial

600 mg vs 400 mg vs 200 mg

daily

No difference between the proportion of patients with

HIV-RNA <400

copies/mL at 24 weeks for

all three doses

Lower doses of efavirenz equally

efficacious

ENCORE 1 Double-blind, placebo-controlled

clinical trial

600 mg vs 400 mg daily

Ongoing 96 week study begun in

August 2011

N.A.

Lanzafame et al. 2012

Clinical cohort with pharmacokinetic

analysis

400 mg daily HIV-RNA persistently < 50 copies/mL with improved

safety

Viral efficacy with improved safety

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Antiretroviral agent Reference Method Doses studied Outcome Conclusion

Atazanavir Avihingsanonet al. 2009

Pharmacokinetic analysis of Thai patients

300 mg plus 100 mg of RTV vs 200 mg plus 100

mg of RTV daily

Same efficacy and plasma atazanavir drug

levels as seen in Caucasians on 300/100

mg daily

200 mg plus 100 mg of ritonavir dosing sufficient in

Thai patients

Giola et al. 2008 Pharmacokinetic analysis of Caucasian patients

300 mg plus 100 mg of RTV vs 200 mg plus 100

mg of RTV daily

Same efficacy of standard dose of

atazanavir (300/100 mg daily)

Reduction of side-effect (hyperbilirubinemia) and

persistence of viral control

Darunavir Lanzafame et al. 2011

Clinical case series with pharmacokinetic analysis

600 mg of darunavir plus 100 mg of ritonavir daily

HIV-RNA persistently < 50 copies/mL

Viral efficacy of lower dose

Lopinavir Murphy et al. 2001 Prospective, randomised, double-blind trial

400 mg plus 100 mg vs 200 plus 100 mg of RTV

100% of patients on lower dose had

suppressed viral load (HIV-RNA < 50

copies/mL) vs 50% on higher dose

Better virological outcome probability related to greater tolerability of lower dose than

standard dose

Hill et al. 2009 Pharmacokinetic meta-analysis 200/50 mg twice daily vs 200/150 mg twice daily vs 400/100 mg twice

daily

200/150 mg twice daily dose of

lopinavir/ritonavir showed similar lopinavir

plasma levels to the standard dose

Higher ritonavir dose can increase plasma concentration

of lopinavir

Ramautarsing et al. 2012

Pharmacokinetic analysis of Thai patients

200/50 mg twice daily Most Thai patients had inadequate lopinavir

plasma concentrations but undetectable HIV-

RNA at week 12

Reduced lopinavir and ritonavir doses do not allow adequate

lopinavir plasma concentrations

Lattuada et al. 2011 Clinical case series with pharmacokinetic analysis

200/50 mg twice daily Viral efficacy at 12 months even though not

all patients had adequate lopinavir

plasma concentrations

Reduced lopinavir and ritonavir doses allow persistent control

of viral replication

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From: Andrew Hill,

Curr Opin HIV AIDS 2013; 8: 34-40.

Page 41: Treatment optimisation. Dose optimisation of antiretrovirals

From: Andrew Hill,

Curr Opin HIV AIDS 2013; 8: 34-40.

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Pharmacokinetic parameters of tenofovir aredose proportional and reductions in plasmaHIV-1 RNA are dose-related at doses of 75 to300 mg daily

It could be worthwhile to test tenofovir at areduced dose of 225 or 250 mg daily

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Pill "A" TDF/3TC/EFV400 $100

Pill "B" DRV400/r/DTG $250

Two pills, used in sequence

Simple treatment rule – task shifting

No overlapping drug resistance

Mass generic production

Low cost: $100 and $250 per person-year

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DRV/r: can we switch to a 400/100 mg OD dose?

FDA approved dose of DRV/r is 600/100 mg BID for PI pre-treated

patients, 800/100 mg OD for PI naïve patients (ODIN)

Non-dose proportional PK: Cmin for 400/100 mg OD is only 33% lower

than for 800/100 mg OD (POWER 1 and 2 trials)

In the POWER trials, doses of 400/100 mg OD to 600/100 mg BID were

equally effective for patients sensitive to DRV. Dose-response only seen

for DRV resistant patients.

No dose-finding studies have ever been run in PI naïve patients

Pilot study shows efficacy for 600/100 mg OD, other trials being started

Page 45: Treatment optimisation. Dose optimisation of antiretrovirals

POWER trials: %HIV RNA >1 log reduction at Week 24, by dose and baseline DRV resistance

Katlama C et al AIDS 2007, 21: 395-402

Haubrich et al AIDS 2007, 21: F11-F18

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4

DRV sensitive DRV resistant

400/100 800/100 400/100 600/100

OD OD BID BID

400/100 800/100 400/100 600/100

OD OD BID BID

DRV/r dose group DRV/r dose group

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DRV/r 600/100 OD + 2NRTIs: 12 naïve patients ___________________________________________________________________________

Patient RNA BL RNA FU Time DRV Cmin

___________________________________________________________________________

Naïve 85,501 <50 20 months 2866

Naïve 115,853 <50 19 months 3140

Naïve 334,500 <50 10 months 3627

Naïve 154,000 <50 24 months 2553

Naïve 87,350 <50 18 months 3824

Naïve 88,110 <50 19 months 1700

Naïve 34,793 <50 12 months 1268

Naïve 4,526 <50 18 months 3732

Naïve 235,520 <50 20 months 2019

Naïve 7,251 <50 15 months 2818

Naïve 63,244 <50 16 months 4562

Naïve 397,932 <50 5 months no data

____________________________________________________________________Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]

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DRV/r 600/100 OD+2NRTIs: 7 pre-treated patients

___________________________________________________________________________

Prior ARV’s RNA BL RNA FU Time DRV Cmin

___________________________________________________________________________

TDF/FTC/FPV/r 33,250 <50 55 months 2143

ZDV/3TC/TDF 15,226 <50 55 months 4518

TDF/FTC/FPV/r 586 <50 43 months 844

TDF/FTC/ATV/r 8,450 <50 38 months no data

TDF/FTC/LPV/r 11,426 <50 38 months no data

TDF/FTC/FPV 119 <50 22 months no data

TDF/FTC/FPV/r 112 <50 20 months no data

____________________________________________________________________

Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]

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South Africa: DRV/r 400/100 OD trial

n=200

HIV RNA <50

on 2NRTI +

LPV/r

Randomised, 48 weeks

South Africa (Francois Venter)

Funding approval phase

2 NRTI + DRV/r 400/100 OD

2 NRTI + LPV/r 400/100 OD

Page 49: Treatment optimisation. Dose optimisation of antiretrovirals

France: DRV/r 400/100 OD trial

n=100

HIV RNA <50

on stable

treatment

2 NRTI + DRV/r 400/100 OD

Single-arm, 48 weeks (Jean-Michel Molina)

Funding: approved by ANRS

Starting in 4Q2014

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SL2: Registration study

NRTI/NNRTI

failures

n=600

Africa / SE

Asia

Randomised, 96 weeks

Target countries introducing viral load – identify VFs

Powered for non-inferiority: FDA, PEPFAR and WHO approval

TDF/FTC + DRV/r 800/100 OD

n=300

DTG + DRV/r 400/100* OD

n=300

*or 50mg booster?

Page 51: Treatment optimisation. Dose optimisation of antiretrovirals

Higher risk of treatment-emergent drugresistance

Under-exposure leading to virological failure

Reduced forgiving of nonadherencecompared with the standard dose

Less ability to withstand drug-druginteractions which lower exposures

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Reduction in adverse events

Improved tolerability

Better quality of life

Better adherence to treatment

Page 53: Treatment optimisation. Dose optimisation of antiretrovirals

It is urgent to implement reasonably large, well-powerednon-inferiority trials comparing lower doses and thecurrently used ones, and we think that it would be in thebest interest even of drug companies and regulatoryagencies to propose and fund such trials, as it is ultimatelymore convenient to access a wider patient population.These trials should also consider economic data, in order toanalyse real life-based models, and would also allow toreconsider currently established relationships betweenplasma levels and efficacy of antiretrovirals questioned bysome studies (Langmann et al. 2002).

Page 54: Treatment optimisation. Dose optimisation of antiretrovirals

Dose optimisation of antiretrovirals

should be further explored as a

strategy to improve tolerability and

decrease costs especially in low and

middle income countries